Renewal is requested for support of projects addressing the nature of normal and pathophysiological mechanisms associated with mammalian primary afferent neurons whose signals contribute to nociception and pain. The overall aim is to provide new information useful for better understanding of primary afferent-spinal cord mechanisms and improved strategies for prevention and treatment of pain. The work concerns two main issues: a) the processes underlying the development of a novel adrenergic excitation of cutaneous nociceptors after peripheral nerve injury, a change shown by recent work to mimic features of human reflex sympathetic dystrophies; b) the parts played and functional interrelations of excitatory amino acids (EAA), purines (ATP and adenosine and somatostatin in synaptic action between central processes of the population of afferent fibers concerned with pain mechanisms and neurons of the superficial spinal dorsal horn. Electrophysiological and molecular biological experiments are to address: 1) the relationship between interruption of the sympathetic efferent innervation and the induction of adrenergic excitation of nociceptors; ii) the generic nature of partial peripheral nerve damage on the responsiveness of primary nociceptors; iii) the possibility that the development of nociceptor adrenergic excitation is the result of novel induction or up-regulation of adrenergic receptor expression in DRG neurons; iv) the transmembrane events associated with adrenergic excitation of nociceptors; v) the relationship between synaptic excitation and inhibition of particular dorsal horn neurons from thin primary afferent neurons and actions attributable to ATP, adenosine, somatostatin and excitatory amino acids. All of the experiments employ tissue from or preparations of purpose-bred animals (rodents, domestic rabbits). Action of adrenergic agonists/antagonists will be tested on discharges of functionally- identified nociceptors after sympathetic or peripheral nerve injury and on transmembrane recordings from dorsal root ganglion neurons in vitro. Evaluation of purine, somatostatin and excitatory amino acids agonists/antagonists would employ whole-cell patch recordings from spinal cord slices in vitro and from DRG neurons in organotypic culture. Effects of nerve/sympathetic lesions on DRG receptor expression will compare mRNA determination on DRG neurons from control and nerve damaged distributions by in situ hybridization histochemistry.